Project Summary/Abstract Solid tumors cannot grow beyond a few millimeters in size without the support of co-opted stromal cells. The function of different stromal cells in the tumor microenvironment may be subverted in ways that are beneficial for tumor progression. Examples are the tumor-induced and specific polarization of immune/inflammatory cells, conversion of fibroblasts into tumor-supportive myofibroblasts, and dysfunctional tumor endothelial cells. Irregular and hyper-permeable vasculature occurs early when only a few hundred-tumor cells are present. Leaky tumor blood vessels deposit fibrin in a perivascular niche that forms scaffolds for tumor cell growth and invasion as well as sparks angiogenesis. Using a miRNA screen of freshly isolated TECs, I identified a TGF?-regulated miRNA (miR-30c) that controls vascular-directed fibrinolysis in tumors. miR-30c is increased in TECs relative to normal endothelial cells (NECs) whereas its target PAI-1 (a fibrinolysis inhibitor) is strikingly decreased. TECs secrete less PAI-1 and they rapidly degrade fibrin scaffolds resulting in aberrant in vitro sprouting. However, TGF? and miR-30c antagomiRs reduce miR-30c expression which re-instates PAI-1 secretion, diminishes fibrinolysis, and ?normalizes? TEC sprouting in vitro. miR-30c antagomiRs coupled to vascular-tropic nanoparticles enforce vascular-specific PAI-1 expression and strikingly promote robust orthotopic mammary tumor growth in vivo. Thus, manipulation of vascular-specific expression of miR-30c in tumors promotes tumor growth likely due to enhanced fibrin-mediated angiogenesis. I propose an axis between TGF?, miR-30c and PAI-1 in TECs controls the rate of perivascular fibrinolysis and is therefore an important effector of tumor angiogenesis and progression.